Free radicals are ubiquitous in our body and are generated by normal physiological processes, including aerobic metabolism and inflammatory responses, to eliminate invading pathogenic microorganisms. Chronic inflammation can increase cancer risk. We are investigating the interaction between nitric oxide (NO&#8729;) and p53 as a crucial pathway in inflammatory-mediated carcinogenesis. We have shown that the p53 tumor suppressor network is a key responder to microenvironmental components of chronic inflammatory stress including nitric oxide, hydroxyl ions, hypoxia, and DNA replication arrest due to DNA damage by endogenous free radicals. Superoxide fluxes also limit NO&#8729; signaling. Chronic inflammation activates the p53 tumor suppressor network and inactivates it by mutation of p53. In addition, chronic inflammation disables the RB tumor suppressor network by hyperphosphorylation of the RB protein, allowing the release of the E2F1 transcription factor. We are also comparing the role of inflammation in colon carcinogenesis in ulcerative colitis versus Crohn's disease. Animal models are a critical facet of our integrative biology strategy, hence we have utilized genetic knockouts, e.g., p53 and inducible nitric oxide synthase, to investigate mechanisms of inflammation-associated cancer. Modest increases in NO&#8729; cause growth arrest and apoptosis to delay tumor formation, whereas higher NO&#8729; amounts are associated with inflammation and increased tumor formation. We will also explore the hypothesis that the increased cancer risk with obesity is related to a proinflammatory state.